Tetrahydroimidazo(1,5-D)[1,4]oxazepine derivative

Patent metadata

Field	Value
Publication number	US-9458176-B2
Application number	US-201414190356-A
Country	US
Kind code	B2
Filing date	Feb 26, 2014
Priority date	Feb 28, 2013
Publication date	Oct 4, 2016
Grant date	Oct 4, 2016

Abstract

A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof works as an mGluR2 antagonist, and is applicable as a therapeutic agent for neurological disorders related to glutamate dysfunction and diseases involving the mGluR2, such as Alzheimer's disease:

wherein R is a hydrogen atom, a C 1-6 alkyl group or the like, R 1 is a C 1-6 alkyl group, a C 1-6 alkoxy group or the like, R 2 is a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or the like, R 3 is a hydrogen atom, a C 1-6 alkyl group or the like, and R 4 is a C 1-6 alkyl group or the like.

First claim

What is claimed is:

1. A compound represented by the following formula (I) or a pharmaceutically acceptable acid addition salt thereof:

wherein R is a hydrogen atom or a C 1-6 alkyl group optionally substituted with 1 to 3 fluorine atoms, wherein
when R is a hydrogen atom,
R 1 is a chlorine atom, a bromine atom, a trifluoromethyl group, an ethyl group, a trifluoromethoxy group, a methoxy group substituted with a phenyl group, a methoxy group substituted with a C 3-8 cycloalkyl group, an ethoxy group optionally substituted with 1 to 3 fluorine atoms, or C 3-8 cycloalkyloxy group,
R 2 is a fluorine atom, a chlorine atom, a methyl group optionally substituted with 2 to 3 fluorine atoms, a methoxy group optionally substituted with 1 to 3 fluorine atoms, or an ethoxy group optionally substituted with 1 to 3 fluorine atoms,
R 3 is a hydrogen atom or a methyl group, and
R 4 is a fluorine atom or a methyl group optionally substituted with 1 to 3 fluorine atoms, or

when R is a C 1-6 alkyl group optionally substituted with 1 to 3 fluorine atoms,
R 1 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group optionally substituted with 1 to 3 fluorine atoms, a C 1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from a fluorine atom and a C 3-8 cycloalkyl group, a C 3-8 cycloalkyloxy group, or a 4- to 6-membered heterocycloalkyloxy group,
R 2 is a hydrogen atom, a cyano group, a halogen atom, a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from a fluorine atom and a hydroxyl group, or a C 1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from a fluorine atom, a C 3-8 cycloalkyl group and a 4- to 6-membered heterocycloalkyl group,
R 3 is a hydrogen atom or a C 1-6 alkyl group, and
R 4 is a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from a fluorine atom and a hydroxyl group, or a C 1-6 alkoxy group.

2. The compound or a pharmaceutically acceptable acid addition salt thereof according to claim 1 , wherein
R is a C 1-6 alkyl group optionally substituted with 1 to 3 fluorine atoms,
R 1 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group optionally substituted with 1 to 3 fluorine atoms, a C 1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from a fluorine atom and a C 3-8 cycloalkyl group, a C 3-8 cycloalkyloxy group, or a 4- to 6-membered heterocycloalkyloxy group,
R 2 is a hydrogen atom, a cyano group, a halogen atom, a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from a fluorine atom and a hydroxyl group, or a C 1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from a fluorine atom, a C 3-8 cycloalkyl group and a 4- to 6-membered heterocycloalkyl group,
R 3 is a hydrogen atom or a C 1-6 alkyl group, and
R 4 is a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from a fluorine atom and a hydroxyl group, or a C 1-6 alkoxy group.

3. The compound or a pharmaceutically acceptable acid addition salt thereof according to claim 2 , wherein R is a methyl group, an ethyl group, a fluoromethyl group or a difluoromethyl group.

4. The compound or a pharmaceutically acceptable acid addition salt thereof according to claim 3 ,
wherein R 1 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, an ethyl group, a 1,1-difluoroethyl group, a methoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, an ethoxy group, a 2-fluoroethoxy group, a 2-propyloxy group, a cyclopropylmethoxy group, a cyclopropyloxy group or an (oxetan-3-yl)oxy group.

5. The compound or a pharmaceutically acceptable acid addition salt thereof according to claim 4 ,
wherein R 2 is a hydrogen atom, a cyano group, a fluorine atom, a chlorine atom, a methyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a hydroxymethyl group, an ethyl group, a methoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, an ethoxy group, a 2-fluoroethoxy group, a 2-propyloxy group, a cyclopropylmethoxy group, a cyclobutylmethoxy group or a (tetrahydro-2H-pyran-4-yl)methoxy group.

6. The compound or a pharmaceutically acceptable acid addition salt thereof according to claim 5 , wherein R 3 is a hydrogen atom or a methyl group.

7. The compound or a pharmaceutically acceptable acid addition salt thereof according to claim 6 , wherein R 4 is a methyl group, a fluoromethyl group, a difluoromethyl group, a hydroxymethyl group or a methoxy group.

8. The compound or a pharmaceutically acceptable acid addition salt thereof according to claim 2 , wherein
R is a methyl group optionally substituted with 1 to 2 fluorine atoms,
R 1 is a hydrogen atom, a chlorine atom, a methyl group optionally substituted with 1 to 3 fluorine atoms, an ethyl group, a C 1-6 alkoxy group optionally substituted with 1 to 3 fluorine atoms, or a C 3-6 cycloalkyloxy group,
R 2 is a cyano group, a chlorine atom, a C 1-6 alkyl group optionally substituted with 1 to 3 fluorine atoms, or a C 1-6 alkoxy group optionally substituted with 1 to 3 fluorine atoms,
R 3 is a hydrogen atom or a methyl group, and
R 4 is a methyl group optionally substituted with 1 to 3 fluorine atoms.

9. A compound selected from the group consisting of the following compounds or a pharmaceutically acceptable acid addition salt thereof:
(R)-3-(4-chloro-3-methoxyphenyl)-1-(2,6-dimethylpyridin-4-yl)-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine,
(R)-1-(2,6-dimethylpyridin-4-yl)-3-(3-methoxy-4-(trifluoromethyl)phenyl)-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine,
(R)-6-methyl-3-(3-methyl-4-(trifluoromethoxy)phenyl)-1-(2-methylpyridin-4-yl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine,
(R)-3-(4-(difluoromethoxy)-3-methylphenyl)-1-(2,6-dimethylpyridin-4-yl)-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine,
(R)-3-(4-(difluoromethoxy)-3-methylphenyl)-6-methyl-1-(2-methylpyridin-4-yl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine,
(S)-1-(2,6-dimethylpyridin-4-yl)-6-(fluoromethyl)-3-(3-methoxy-4-(trifluoromethoxy)phenyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine,
(S)-6-(fluoromethyl)-3-(3-methoxy-4-(trifluoromethoxy)phenyl)-1-(2-methylpyridin-4-yl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine,
(R)-3-(3-chloro-4-cyclopropoxyphenyl)-1-(2,6-dimethylpyridin-4-yl)-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine,
(R)-3-(4-cyclopropoxy-3-methylphenyl)-1-(2,6-dimethylpyridin-4-yl)-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine,
(R)-3-(3-chloro-4-(difluoromethoxy)phenyl)-6-methyl-1-(2-methylpyridin-4-yl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine,
(S)-3-(4-cyclopropoxy-3-methylphenyl)-1-(2,6-dimethylpyridin-4-yl)-6-(fluoromethyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine,
(R)-3-(3-methoxy-4-(trifluoromethoxy)phenyl)-6-methyl-1-(2-methylpyridin-4-yl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine,
(R)-1-(2,6-dimethylpyridin-4-yl)-3-(3-methoxy-4-(trifluoromethoxy)phenyl)-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine,
(S)-3-(4-(difluoromethoxy)-3-methylphenyl)-1-(2,6-dimethylpyridin-4-yl)-6-(fluoromethyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine,
(S)-1-(2,6-dimethylpyridin-4-yl)-6-(fluoromethyl)-3-(3-methoxy-4-(trifluoromethyl)phenyl)-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine,
(R)-3-(3-chloro-4-(difluoromethoxy)phenyl)-1-(2,6-dimethylpyridin-4-yl)-6-methyl-5,6,8,9-tetrahydroimidazo[1,5-d][1,4]oxazepine,
(R)-3-(3-chloro-4

Assignees

• Eisai R&D Man Co Ltd

Inventors

• Takaishi Mamoru
• Sato Nobuhiro
• SHIBUGUCHI Tomoyuki
• Motoki Takafumi
• Takahashi Yoshinori
• Sasaki Takeo
• Braunton Alan

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/553 Primary

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title